Schizophrenia

Question 1

Define schizophrenia

Answer 1

1. A long-term mental disorder of a type involving a breakdown in the relation between thought, emotion, and behaviour, leading to faulty perception, inappropriate actions and feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a sense of mental fragmentation

Question 2

How is schizophrenia diagnosed

Answer 2

1. No reliable, consistent or useful body fluid biomarker
2. Principally clinical observation and history (DSM)
3. Symptoms - presence of 2 or more over 1 month
4. Social - one or more major areas (work, interpersonal relationships, self-care) below level prior to illness.
5. Duration - signs persist for at least 6 months
6. Other possible diagnostic markers – see later
7. Biomarker changes in brain electrical activity
8. Biomarker changes in brain structure

Question 3

What are the symptoms from which 2 need to present for over 1 month

Answer 3

1. delusions
2. hallucinations
3. disorganised speech
4. grossly disorganised/catatonic behaviour
5. affective flattening, alogia, or avolition (negative symptoms)

Question 4

What are the positive symptoms of schizophrenia

Answer 4

1. increase in abnormal active behaviours including
2. hallucinations
3. delusions
4. disordered thoughts
5. language abnormality
6. motor disorders

Question 5

What are the negative symptoms of schizophrenia

Answer 5

1. absence of normal active behaviours occur prior to positive symptoms
2. affective blunting- emotional responses
3. avolition
4. anhedonia
5. poverty of speech
6. social withdrawal
7. neglect of hygiene

Question 6

What are the Cognitive symptoms of schizophrenia

Answer 6

1. disturbance of normal thought processes
2. poor executive function and decision making
3. recognition deficits
4. memory problems
5. attention deficits

Question 7

What is the prognosis for schizophrenia

Answer 7

1. 25% Remit completely; no further symptoms
2. 25% Good social recovery; some symptoms persist
3. 25% Partial social recovery; persistence of symptoms
4. 25% Steady downhill course; social and personality deterioration

Question 8

Describe schizophrenia epidemiology

Answer 8

1. Prevalence ~1%
2. 10% suicide risk – 40% single attempt
3. Onset
4. ♂: median 26 yrs
5. ♀: median 29 yrs
6. ♂:♀ ~1.3:1
7. Increased prevalence in lower economic strata

Question 9

What are the different courses of schizophrenia

Answer 9

1. Relapsing and remitting: episodic

2. Chronic and progressive

Question 10

What is the Aetiology of schizophrenia

Answer 10

1. Clearly complex but largely unknown
2. genetic
3. environmental
4. structural brain changes

Question 11

Why is schizophrenia thought to have genetic factor

Answer 11

1. strongly inherited – 50% in monozygotic twins

2. no specific gene identified - many genes implicated

Question 12

What are the environmental factors of schizophrenia

Answer 12

1. no specific factors implicated
2. pregnancy and delivery complications
3. prenatal and childhood virus infection
4. urban birth and residence
5. psychosocial factors (dysfunctional family environment)

Question 13

What are the structural brain changes that can lead to schizophrenia

Answer 13

1. developmental disruption of neuronal migration
2. enlarged ventricles
3. reduced regional cerebral volumes
4. loss of neurones
5. reduced network and functional activity

Question 14

What are structural changes that act as biomarkers in MRI scans

Answer 14

1. Ventricles in in schizophrenic patients are enlarged
2. With chronic schizophrenia- lateral ventricles continue to increase over time
3. Loss of neuronal tissue associated with schizophrenia

Question 15

What are biomarkers in EEG and how do you carry out an EEG

Answer 15

1. Changes in gamma behaviour
2. Take individual and subject to a buzzer sound and measure EEG
3. Can’t discern common change in EEG from individual EEG
4. But if you add repeated EEG recordings together- noise cancels out and left with common wavelength related to buzzer
5. Deficit in power in areas associated with memory and recall

Question 16

What pathways are involved with schizophrenia

Answer 16

1. All about excess dopamine
2. nigrostriatal pathway
3. Mesolimbic pathway (A10 from VTA)
4. Mesocortical pathway (A10 from Ventral Tegmental Area)
   5 . Retrorubral field (A8)

Question 17

How is the nigrostriatal pathway involved

Answer 17

1. motor actions (A9 from substantia nigra pars compacta)

Question 18

How is the Mesolimbic pathway involved

Answer 18

1. nucleus accumbens amygdala
2. hippocampus
3. entorhinal cortex
4. cingulate cortex
5. Positive symptoms
6. perception
7. emotions
8. memory

Question 19

How is the Mesocortical pathway involved

Answer 19

1. prefrontal cortex
2. cingulate gyrus
3. Negative symptoms
4. motivation
5. volition
6. cognition
7. planning
8. social behaviour

Question 20

How can drugs cause schizophrenia

Answer 20

1. cocaine and amphetamine release DA
2. chronic abuse can elicit toxic psychosis
3. paranoid delusions
4. hallucinations
5. compulsive behaviour
6. exacerbates positive symptoms

Question 21

What does L-DOPA do

Answer 21

1. L-DOPA increases DA levels

2. delusions and hallucinations

Question 22

Describe how antipsychotic/neuroleptic drug are associated with schizophrenia

Answer 22

9) action correlates with D2 DA receptor block – increase in dopamine receptors- a factor in schizophrenia or increased because of it
a) D2 DA gene - risk factor in schizophrenia
b) DA receptors may be increased in schizophrenics

Question 23

Describe how antipsychotic/neuroleptic drug are associated with schizophrenia

Answer 23

1. action correlates with D2 DA receptor block –
2. increase in dopamine receptors- a factor in schizophrenia or increased because of it
3. D2 DA gene - risk factor in schizophrenia
4. DA receptors may be increased in schizophrenics

Question 24

What does Neuroleptic efficacy correlate with

Answer 24

1. Neuroleptic efficacy correlates with D2 receptor blockade
2. Tight correlation between average clinical dose of antipsychotic compounds and D2 binding affinity
3. Lower affinity- need higher dosage
4. No correlation with other receptors

Question 25

What are some typical (first generation) antipsychotics

Answer 25

1. High affinity D2-receptor antagonists 2. phenothiazines - chlorpromazine, thioridazine, fluphenazine 3. butyrophenones - haloperidol 4. thioxanthenes – chlorprothixene 5. dibenzodiazepines – clozapine 6. Serious side effects

Question 26

What are typical (first generation) antipsychotics effective against

Answer 26

1. Effective ONLY against positive symptoms

Question 27

What are some DA associated side effects of typical (first generation) antipsychotics

Answer 27

1. DA related include hormonal and extrapyramidal motor 2. pseudoparkinsonism (early Parkinson’s like) 3. tardive dyskinesia (late Huntington’s like) 4. other motor effects (akathisia, dystonia) 5. increased prolactin release – sexual dysfunction

Question 28

What are some Non-DA associated side effects of typical (first generation) antipsychotics

Answer 28

1. sedation - antihistamine, anticholinergic 2. hypotension – central adrenergic 3. peripheral autonomic – blurred vision, dry mouth, constipation

Question 29

What are some Atypical (second generation) antipsychotics

Answer 29

1. Relatively low affinity for D2 2. Benzamides: lanzapine, Quetiapine, Risperidone, Ziprasidone, Quitiapine, Aripiprazole 3. Also Clozapine

Question 30

What symptoms are Atypical (second generation) antipsychotics effective against

Answer 30

1. Effective against both positive and negative 2. High affinity at 5HT2 3. High ratio 5HT2:DA may be desirable

Question 31

What are side effects of Atypical (second generation) antipsychotics

Answer 31

1. Less side effects than Typicals, especially motor effects. 2. but other side effects 3. weight gain 4. diabetes

Question 32

What are problems with DA treatments

Answer 32

1. Serious dopaminergic side effects 2. many neuroleptics only control positive symptoms 3. DA block immediate – clinical onset 6-8 weeks – adapative changes 4. drugs block many other receptors 5. muscarinic, histaminergic, alpha-noradrenergic

Question 33

What role does 5HT play in schizophrenia and how could this be used

Answer 33

1. Increased levels in schizophrenics 2. LSD - 5HT agonist induces hallucinations, cognitive impairment, aggression 3. 5HT metabolites (Dimethyltryptamine) hallucinogenic 4. many neuroleptics are potent 5HT2 receptor blockers

Question 34

What happens in typical antipsychotics

Answer 34

1. Typical antiphsycotic have high affinity for D2 2. When complete D2 blockade can see antipshycotic affect + motor side effects 3. 5HT neurones impinge on dopanergic nerve terminals 4. When releases 5HT it reduces release of dopamine from nerve terminal

Question 35

What happens with atypical antipsychotics

Answer 35

1. Low affinity for D2 2. High affinity for 5HT2A 3. Antipsychotic will block 5HT2A Heteroreceptors on dopaminergic nerve terminals 4. Reduces the signal from receptors which under normal circumstances would induce dopamine release 5. Break on dopamine release is removed 6. Increase dopamine release 7. Partial blockade- achieves antipsychotic effects but with reduced motor side effects

Question 36

How could glutamate affect schizophrenia and be used to treat

Answer 36

1. Neurodevelopmental change – glutamate neurones affected 2. Disordered migration - abnormal circuits 3. Neuronal and synaptic loss 4. NMDA antagonists e.g. ketamine, phencyclidine are psychotomimetic 5. NMDA receptor knockout - social withdrawal in mice 6. Reduced glutamate in CSF 7. Loss of cortical glutamate receptors in post mortem schizophrenics- suggests that blockade of glutamergic system in brain may induce psychotic episode

Question 37

Describe DA-glutamate interaction and how this can lead to positive symptoms

Answer 37

1. DA-glutamate interaction – positive symptoms 2. glutamate neurons in cortex excite GABA in VTA by NMDA receptors 3. input from NMDA which is stimulatory stimulates inhibitory GABAergic neuron 4. This reduces activity in mesolimbic dopamine neurone into nucleus accumbens 5. In schizophrenia Glutamatergic neurons are reduced 6. loss of excitation reduces inhibition in VTA, Less inhibitory effect on GABAergic interneuron 7. loss of inhibition causes excess DA release in mesolimbic path

Question 38

What is lost in a schizophrenic

Answer 38

1. Ordered distribution of neurons is lost in schizophrenic 2. Individual neurons in schizophrenic brains show shorter branches in dendritic tree than normal 3. The number of spines – sites of incoming synaptic contact from other neurons- far fewer in schizophrenic subjects

Question 39

Describe how DA-glutamate interaction could result in negative symptoms

Answer 39

1. Glutamatergic neuron makes direct contact with mesocortical dopanergic neuron – excitatory 2. Maintains activity of dopanergic output 3. In Schizophrenia Glutamatergic neurons lost 4 Excitation of dopanergic neuron goes down 5. Suggests reduction of dopamine